Conserved noncoding cis elements associated with hibernation modulate metabolic and behavioral adaptations in mice.

Area of Science:

• Genomics
• Evolutionary Biology
• Metabolic Research

Background:

• Cis-regulatory elements (CREs) are crucial for phenotypic diversity, but their causal links to function are not fully understood.
• Conserved CREs associated with mammalian hibernation and metabolic flexibility offer insights into evolutionary adaptation.

Purpose of the Study:

• To elucidate the functions of conserved CREs involved in the evolution of mammalian hibernation and metabolic flexibility.
• To investigate the causal relationships between CREs and their downstream effects on gene expression and metabolic processes.

Main Methods:

• Genomic analyses to identify topologically associated domains (TADs) with convergent changes in hibernators, focusing on the Fat Mass & Obesity (Fto) locus.
• Identification of genetic circuits and hibernation-linked CREs within TADs that form regulatory contacts with neighboring genes.
• Experimental deletion of individual CREs in mice to assess their impact on gene expression and physiological traits.

Main Results:

• TADs, including the Fto locus, showed enrichment for convergent evolutionary changes in hibernators.
• Genetic circuits and CREs associated with hibernation and metabolic responses were identified, forming regulatory contacts with adjacent genes.
• Deletion of specific CREs in mice led to differential alterations in Fto, Irx3, and Irx5 expression, impacting downstream gene programs, metabolism, torpor, obesogenesis, and foraging.

Conclusions:

• Convergent evolution in hibernators highlights functional genetic mechanisms of metabolic control.
• Single CREs can encode multiple regulatory effects, influencing diverse physiological processes such as metabolism, hibernation, and obesity.
• This study provides a framework for understanding how CREs contribute to adaptive phenotypic evolution.